Interview with Dr. Robert A. Kyle

Where would you recommend Freelite™ in clinical practice?

A patient with nonsecretory myeloma would benefit from the use of Freelite. We believe that this test will allow us to reclassify those patients who look like they have nonsecretory myeloma. In fact, we found that the Freelite assay is abnormal in about two thirds of patients with nonsecretory myeloma diagnosed on the basis of immunofixation.

Patients with light chain multiple myeloma and primary amyloidosis with no measurable M-protein should have a monoclonal free light chain determination because the vast majority of patients do have an abnormality. In short, clinically, any patient who has a plasma cell proliferative disorder, but no evidence of a measurable monoclonal protein in the serum or in the urine should have a free light chain initially.

The free light chain test is also useful in prognostication of monoclonal gammopathy of undetermined significance (MGUS). In our experience, about one-third of patients with MGUS will have an abnormal free light chain ratio. Freelite is an independent risk factor for disease progression. Risk factors for the development of disseminated multiple myeloma from solitary plasmacytoma of bone are the presence of an abnormal free light chain ratio at the time of the recognition of the solitary plasmacytoma and the persistence of the M-protein after therapy.*

In your clinical practice, do you use the Freelite to screen and diagnose patients along with SPEP or IFE?

Recently, Dr. Katzmann demonstrated in a study¹ that the combination of serum electrophoresis, free light chain determination and immunofixation allows for detection of a monoclonal protein in serum. One does not need to collect a 24-hour urine when one is screening for a monoclonal protein. Out of 428 patients the serum assays were normal in only two patients, one of whom had idiopathic Bence Jones proteinuria and one whose urine sample contained an intact monoclonal immunoglobulin, but whose serum and subsequent urine samples showed no evidence of monoclonal gammopathy. Take note, however, that once a patient has a monoclonal protein detected by examining just the serum, one must collect a 24-hour urine and perform immunofixation to see if a monoclonal protein is present in the urine.

Has the availability of Freelite helped you to effectively clinically monitor your patients?

Monitoring a patient following treatment can be difficult and Freelite may be helpful in that situation. For example, if a patient receives an autologous stem cell transplant followed by a complete response, then the development of an abnormal free light chain ratio would herald the onset of relapse. However, you're not going to treat that patient with the earliest evidence of relapse. We will wait until the patient has symptomatic or near symptomatic disease again before treating the patient.

Is the Freelite test useful in minimal residual disease?

As a matter of fact, the International Myeloma Working Group has defined a "stringent complete response" as having normal free light chain values. Ordinarily, a complete response to therapy in multiple myeloma consists of a negative immunofixation in the serum, a negative immunofixation in the urine, fewer than five percent plasma cells in the bone marrow, and no other evidence of active disease. The next step in the quality of response would be normal free light chain values.

Is sensitivity of the Freelite test useful in patients with AL amyloidosis?

The monoclonal protein in the serum and the urine may be very low in these patients and cannot be accurately measured using electrophoresis. The high sensitivity of Freelite is useful in this situation.

Does the same apply towards monitoring those patients?

Well, yes. For the patient with nonsecretory myeloma and for the patient with amyloid or myeloma where immunofixation is negative, the Freelite assay is helpful in monitoring. But again, I want to emphasize that this is not a clinical indication for therapy. The first indication of relapse in a patient with a complete response may be the appearance of an abnormal free light chain value; however, we would forego treatment until the patient has clinical manifestations of their disease such as anemia, new bone lesions, or hypercalcemia.

And how often do you monitor these patients?

That varies from patient to patient. The longer the patient is in a response state, the less frequently we will monitor him. It depends too on where the patient lives, his anxiety level and other individual considerations. In general, if the patient is asymptomatic and has no evidence of disease, one would examine the patient at two or three month intervals. If the patient is stable with no evidence of disease, one might stretch that out to four or six months, but there is no specific time. There are some patients who are apprehensive and zeroed-in on their health and blood counts and they dictate when they want to be monitored. It is based on the clinical picture of the patient and the comfort level of the patient and clinician.

Dr. Kyle, if you were you to apply the risk stratification model to MGUS patients, how frequently would you follow those patients who are considered to be low risk versus those who are high risk?*

One would want to repeat the protein in two or three months because every once in a while, you'll tumble onto a patient who really has a developing myeloma. At this point, you are looking at a snapshot of the patient's monoclonal protein production, and we would want to know the how rapidly the protein concentration is increasing. So we check two or three months later to make sure that the protein concentration hadn't gone from one gram to two grams, for example, which would indicate disease progression. You'd want to make sure that the protein was stable and not increasing.

In the low risk MGUS patient, you could probably check again in a year's time and after that, maybe, in two to three years.

In the high risk patient, you would examine that patient more frequently. For example, after determining the high risk status of that MGUS patient, I would probably test in two to three months, then, if stable, four or five months after that second visit. If the patient is not progressing, you might do it in six months and then possibly on an annual basis.

How did you initially learn about the Freelite test?

Six or seven years ago, Dr. A.R. Bradwell visited the laboratory, and said he had an antibody that would measure free light chains. I was quite skeptical because over the preceding 30 years I'd seen numerous antibodies that were purported to recognize free light chains but after I tested them I would find that they would actually recognize not only the free light chain, but also the light chain in the intact immunoglobulin. Many were also weak, and did not recognize all of the free light chain that was present in the specimen. So, I became rather jaded and unimpressed with any of the antibodies that claimed that they could measure only free light chains.

Dr. Bradwell, a Professor of Immunology at the University of Birmingham Medical School in England, is a very convincing sort of person. He said that this antibody would work in a nephelometer, allowing for quantification of the results. So, after a long visit, I said to him, "Okay, we'll take a look at your antibody."

Here, at the Mayo Clinic, we have a serum bank of patients who are healthy and on whom we had detailed information such as gender, age, health status, etc. After receiving Dr. Bradwell's antibody, Dr. Jerry Katzmann determined the reference ranges in 282 patients. One interesting result that came from that study was that we found that older patients had higher levels of both kappa and lambda in their serum. Furthermore, when we looked at the renal function of this group we found that above the age of 70 years, renal function decreases, and the ability to catabolize the monoclonal light chain also decreased. Thus, the light chain levels in the serum are higher; however, the ratio remains the same because the reduced renal clearance affects both the kappa and lambda light chains². We have done a number of studies using Freelite, including the population of Olmsted County. It has turned out to be a very valuable and helpful test in clinical medicine.